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Background: Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of a7 or a4ß2-nAChRs and related HSP70/TNFa/iNOS signaling in the interaction. Methods: Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 50- N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated. Results: Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased a7-nAChRs, a4ß2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFa inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in a7/a4ß2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. a7-nAChRs (methyllycaconitine citrate, MLA) or a4ß2-nAChRs (dihydro-ß-erythroidine, DHßE) blockade potentiated the lipopolysaccha- ride enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHßE/ nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA. Conclusions: These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the a7 and a4ß2 types.